The increasing need for methods of synthesizing complex chemical compounds has led, in recent years, to the development of new techniques for synthesizing, and subsequently screening, large numbers of compounds. In general, a highly desirable feature of any new method of synthesis is that the purification of intermediates, and preferably of the final products, be rapid and inexpensive. Crystallization is commonly employed, but not all compounds can be readily crystallized. Chromatographic separation, as required by some older methods, is prohibitively expensive and time-consuming, particularly when performed on large quantities of compounds, or when many impurities are present.
For this reason, synthetic methods that employ solid-phase supports for synthesis of complex molecules have become increasingly popular. The ability to easily handle and purify polymer-supported materials has facilitated the development of combinatorial approaches to pharmaceutical synthesis and screening, and has resulted in a dramatic increase in the number of drug candidates that can be developed and tested in a relatively short period of time.
Solid-phase reactions have certain disadvantages, however, compared to reactions in solution. One disadvantage is the inability to use reactants which are not soluble in the reaction medium (for example, certain catalysts). Another frequent disadvantage is the need to use solvents which are capable of swelling the polymer support. The efficiency and selectivity of a reaction carried out on a solid phase can vary greatly relative to the reaction in solution. For example, yields can be affected, reaction times lengthened, and selectivity (e.g., enantioselectivity or regioselectivity) of a reaction on a solid support can be different from the corresponding solution-phase reaction. Furthermore, the need to ensure complete reaction throughout the heterogeneous reaction mixture can lead to longer reaction times than are required in solution-phase chemistry.